Human alpha interferon comprises a family of more than fifteen proteins with antiviral, antigrowth and immunoregulatory activities Pestka et al., Ann. Rev. Biochem., 56:727 (1987)!. The therapeutic efficacy of human alpha interferons has been established for human cancers and viral diseases. For example, recombinant interferons (IFN alfa-2a, IFN alfa-2b, IFN alfa-2c), cell-line derived interferon (IFN alfa-n1) and interferon derived from leukocytes (IFN alfa-n3) are currently used for the treatment of Condyloma acuminata, hepatitis Weck et al., Am. J. Med., 85(Suppl 2A):159 (1988); Korenman et al., Annal. Intern. Med., 114.:629 (1991); Friedman-Kien et al., JAMA, 259:533 (1988)!, for the regression of some malignancies Baron et al., JAMA, 266:1375 (1991)!, for the treatment of AIDS related Kaposi's sarcoma Physicians Desk Reference, 47th edit., eds. Medical Economics Data, Montvale, N.J., p. 2194 and 2006 (1993)! and are currently being considered for the treatment of human acquired immunodeficiency syndrome (AIDS) either alone or in combination with other antiviral agents Hirsch, Am. J. Med., 85(Suppl 2A):182 (1988)!.
Recombinant interferons can be made by using genetic engineering techniques, for example, in Escherichia coli in large scale Goeddel et al., Nature, 287:411 (1980); Streuli et al., Science, 209:1343 (1980)!. However, genetically engineered interferons are composed of only a single species, which is not post-translationally modified at all or identically to the natural interferons, and which may limit the biological activity of the composition. For example, IFN-.alpha.2 is the sole species in the products Intron.RTM. A (IFN alfa-2b) Schering Plough! and Roferon.RTM. A (IFN alfa-2a) Hoffman-La Roche!.
Interferons derived from natural sources, such as those from human lymphoblastoid, Namalwa, cell line Mizrahi, Meth. Enzymol., 78:54 (1981); Phillips et al., Meth. Enzymol., 119:35 (1986)!, and those from human peripheral blood leukocytes Mogensen et al., Pharmacol. Ther. Part C, 1:369 (1977); Cantell et al., Methods Enzymol., 78:29 (1981); Horowitz, Methods Enzymol., 119:39 (1986)!, are composed of multiple species, each with different structural and biological activity.
Such "natural" interferons are considered by some researchers to provide potentially better therapeutic efficacy than recombinant interferon. For example, natural alpha interferon can be used at a four times lower dosage to treat Condyloma than the recombinant products see, e.g., Physicians Desk Reference, cited above, at pages 1879 and 2194!. The most significant advantage of using natural leukocyte interferon as a therapeutic agent has been its low immunogenecity in patients receiving interferon treatment. It has been documented that patients treated with the recombinant interferons identified above, and lymphoblastoid interferon Wellferon.RTM. IFN alfa-n1 Burroughs Wellcome! have developed neutralizing antibodies to interferon Lok et al., Hepatology, 12:1266 (1990); Jacobs et al., J. Biol. Resp. Mod., 7:447 (1988); Weck et al., J. Interferon Res., 1(Suppl):S37 (1989)!. However, patients treated with leukocyte derived interferon (IFN alfa-n3 or Cantell's partially purified interferon preparation) do not generate detectable serum antibody to interferon Von Wussow et al., Lancet, 2:635 (1987); Liao et al., J. Infect. Dis., 165:757-760 (1992)!. The presence of neutralizing anti-interferon antibodies may potentially block the therapeutic effect of the interferon and therefore may be a significant factor in the course of clinical treatment. However, many of such patients resistent to recombinant alpha interferon have been shown to respond to natural alpha interferon treatment.
Previously reported methods for alpha interferon production from human peripheral blood leukocytes are both inefficient and very costly Mogensen et al., (1977); Cantell et al., (1981); and Horowitz, (1986), all cited above!. Cantell's published method of producing natural alpha interferon from leukocytes results in the generation of a relatively low titer of interferon (60,000 CPE U/ml) from a relatively high cell density (1.times.10.sup.7 cells/ml).
Prior methods of purification of natural alpha interferon also have their limitations. For example, Cantell et al., Meth. Enzymol., 78:499 (1981) describes only the partial purification of human leukocyte interferon on a large scale using sequential precipitation method. The resultant interferon is approximately 1% pure containing multiple interferon species. Berg et al., Meth. Enzymol., 78:487 (1981) describe Sepharose 4B-conjugated monoclonal antibody affinity chromatography for purification of human leukocyte interferon. Finally, Horowitz, (1986), cited above, describes large scale production and purification of human leukocyte interferon from peripheral blood leukocytes. He used either Cantell's precipitation method or NK2 antibody affinity chromatography.
There are increasing numbers of alpha interferon preparations now being used in patients and in clinical trials for various indications. However, all have been characterized by a number of side effects in patients. Such flu-like symptoms include fever, low blood cell counts, gastrointestinal disorders, such as vomiting and diarrhea, renal disorders, pulmonary disorders, allergic reactions, such as bronchospasm or anaphylaxis or skin rashes, hair loss, and infection, which are identified in the product literature for alpha interferons now on the market.
While some of the side effects are minor, they can have serious negative impacts on patients who must take significant doses of the compositions for long periods of time. For example, for certain therapies, e.g., the treatment of AIDS-related Kaposi's sarcoma and a symptomatic AIDS, the dosage at which the interferons are effective produces side effects which are worse than the effects of the disease at certain stages. In clinical trials for these indications, the occurence of the side effects has resulted in patients abandoning the procedure despite its probable long term benefit H C. Lane et al, Annals of Internal Medicine, 112:805 (1990)!.
Thus, there remains a need for an improved alpha interferon composition which can be characterized by very low toxicity and high purity and which can produce minimal side effects in patients undergoing interferon therapy.